WO2000020395A1 - New crystal modification iii of torasemide - Google Patents

New crystal modification iii of torasemide Download PDF

Info

Publication number
WO2000020395A1
WO2000020395A1 PCT/HR1999/000023 HR9900023W WO0020395A1 WO 2000020395 A1 WO2000020395 A1 WO 2000020395A1 HR 9900023 W HR9900023 W HR 9900023W WO 0020395 A1 WO0020395 A1 WO 0020395A1
Authority
WO
WIPO (PCT)
Prior art keywords
torasemide
crystal modification
iii
modification iii
new crystal
Prior art date
Application number
PCT/HR1999/000023
Other languages
French (fr)
Inventor
Darko Filić
Miljenko DUMIČ
Aleksandar Danilovski
Božena Klepić
Ines Fistrić
Marina Orešić
Jasna HORVAT MIKULČIĆ
Original Assignee
Pliva, Farmaceutska Industrija, Dionicko Drustvo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=10946825&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2000020395(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to NZ510898A priority Critical patent/NZ510898A/en
Priority to DK99949272T priority patent/DK1117643T3/en
Priority to IL14215099A priority patent/IL142150A0/en
Priority to SI9930744T priority patent/SI1117643T1/en
Priority to PL99346975A priority patent/PL346975A1/en
Priority to UA2001031966A priority patent/UA72895C2/en
Priority to AU62240/99A priority patent/AU759291B2/en
Priority to AT99949272T priority patent/ATE286024T1/en
Priority to HU0104009A priority patent/HUP0104009A3/en
Application filed by Pliva, Farmaceutska Industrija, Dionicko Drustvo filed Critical Pliva, Farmaceutska Industrija, Dionicko Drustvo
Priority to EEP200100194A priority patent/EE04341B1/en
Priority to DE69922977T priority patent/DE69922977C5/en
Priority to JP2000574512A priority patent/JP2002526532A/en
Priority to SK423-2001A priority patent/SK4232001A3/en
Priority to EP99949272A priority patent/EP1117643B1/en
Priority to BR9915018-2A priority patent/BR9915018A/en
Priority to CA002345789A priority patent/CA2345789A1/en
Publication of WO2000020395A1 publication Critical patent/WO2000020395A1/en
Priority to NO20011633A priority patent/NO317107B1/en
Priority to BG105485A priority patent/BG105485A/en
Priority to HK02102011.9A priority patent/HK1040250B/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • the present invention relates to a new crystal modification of N-(l-methylethyl aminocarbonyl)-4-(3-methyl-phenylamino)-3-pyridinesulfonamide (in the further text of the application designated by its generic name 'Torasemide”), particularly to a new crystal modification III of torasemide. to processes for its preparation, to its use as a raw material for the preparation of the crystal modification I of torasemide and of pharmaceutically acceptable salts of torasemide as well as to pharmaceutical forms containing the said new modification III of torasemide as the active ingredient.
  • Torasemide is a compound with interesting pharmacological properties, which is described in DE patent 25 16 025 (Example 71).
  • a diuretic of Henle's loop it is useful as an agent for preventing heart or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris.
  • asthma hypertension
  • nephroedema pulmonary edema
  • primary and secondary aldosteronism Bartter's syndrome
  • tumours glaucoma
  • decreasing of intraocular pressure decreasing of intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by trauma, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens.
  • polymorphism The ability of a substance to exist in more than one crystal form is defined as polymorphism and these different crystal forms are named "polymorph modifications " ' or "polymorphs".
  • polymorphism is affected by the ability of a molecule of a substance to change its conformation or to form different intermolecular or intramolecular interactions, particularly hydrogen bonds, which is reflected in different atom arrangements in the crystal lattices of different polymorphs.
  • Polymorphism is found in several organic compounds. Among medicaments polymorphism is found in about 70% of barbiturates, 60% of sulfonamides and 60% of steroids and about 50% of medicaments of the said classes are not present on the market in their most stable forms (T. Laird, Chemical Development and Scale-up in the Fine Chemical Industry, Principles and Practices, Course Manual, Scientific Update, Wyvern Cottage, 1996).
  • the different polymorphs of a substance possess different energies of the crystal lattice and, thus, in solid state they show different physical properties such as form, density, melting point, colour, stability, dissolution rate, milling facility, granulation, compacting etc., which in medicaments may affect the possibility of the preparation of pharmaceutical forms, their stability, dissolution and bioavailability and, consequently, their action.
  • Polymorphism of medicaments is the object of studies of inter additiver expert teams [J. Haleblian, W. McCrone, J. Pharm. Sci. 58 (1969) 911 ; L. Borka, Pharm. Ada Helv. 66 (1991) 16; M. Kuhnert-Brandstatter, Pharmazie 51 (1996) 443; H. G. Brittain, J Pharm. Sci. 86 (1997) 405; W. H. Streng, DDT 2 (1997) 415; K. Yoshii, Chem. Pharm. Bull. 45 (1997) 338, etc.] since a good knowledge of polymorphism represents a precondition for a critical observation of the whole process of medicament development.
  • Example 71 of DE 25 16 025 torasemide in a crystal form with melting point 163-164°C is obtained.
  • alkaline solutions of torasemide there are meant an alkaline extract of the original reaction mixture for the synthesis of torasemide, alkaline solutions of any crystal modification I, II or III of torasemide or alkaline solutions of any mutual mixtures of crystal modifications I, II or III of torasemide.
  • water solutions of lithium, sodium and potassium hydroxide as well as water solutions of sodium and potassium carbonate can be used.
  • the acidifying of the alkaline torasemide solutions according to the invention can be performed in inorganic acids such as hydrochloric, sulfuric, phosphoric and nitric acids and in organic acids such as formic, acetic, propionic, oxalic, tartaric, methanesulfonic and p-toluenesulfonic acids.
  • inorganic acids such as hydrochloric, sulfuric, phosphoric and nitric acids
  • organic acids such as formic, acetic, propionic, oxalic, tartaric, methanesulfonic and p-toluenesulfonic acids.
  • the new crystal modification III of torasemide is stable under normal storage conditions as well as at being subjected to increased humidity, which means that it is neither transformed into the unstable modification II of torasemide nor into the stable modification I of torasemide.
  • characteristic spacings between lattice planes designated by »d « and expressed in Angstrom units and their corresponding characteristic relative intensities designated by »I/I 0 « and expressed in % are represented in Table 1.
  • the new crystal modification III of torasemide prepared according to the process of the present invention can be transformed by the use of common processes to the crystal modification I of torasemide, i.e. it can be used as a starting material for the preparation of known crystal modification I of torasemide.
  • the new crystal modification III of torasemide prepared according to the invention can be transformed to pharmaceutically acceptable salts of torasemide by the use of common processes.
  • the new crystal modification III of torasemide is prepared according to the process of the present invention in the form of a flowable crystal powder of a prismatic pertaining to the process of the present invention in the form of a flowable crystal powder of a prismatic pertaining to the process of the present invention in the form of a flowable crystal powder of a prismatic pertaining to the process of the present invention in the form of a flowable crystal powder of a prismatic pertaining to the process of the present invention in the form of a flowable crystal powder of a prismatic pertaining, which exhibits flowability, i.e. it comes in a "free flow" form, wherein no static charge accumulation occurs.
  • the new crystal modification III of torasemide prepared according to the process of the present invention can be used as a suitable torasemide form as a diuretic as well as an agent for preventing heart or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris, asthma, hypertension, nephroedema, pulmonary edema, primary and secondary aldosteronism, Bartter's syndrome, tumours, glaucoma, for decreasing intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by trauma, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens.
  • the present invention also relates to pharmaceutical forms such as tablets containing the new crystal modification III of torasemide as the active ingredient combined with one or more pharmaceutically acceptable additives such as sugar, starch, starch derivatives, cellulose, cellulose derivatives, mould release agents, and antiadhesive agents and possibly agents for flowability regulation.
  • pharmaceutically acceptable additives such as sugar, starch, starch derivatives, cellulose, cellulose derivatives, mould release agents, and antiadhesive agents and possibly agents for flowability regulation.
  • the starting materials for the process of the present invention i.e. the alkaline extract of the original reaction mixture for torasemide synthesis can be prepared according to DE 25 16 025, whereas the modifications I and II of torasemide can be prepared according to Ada Cryst. B34 (1978), 1304-1310.
  • Example 1 The present invention is illustrated but in no way limited by the following Examples.
  • Example 1 The present invention is illustrated but in no way limited by the following Examples.
  • the original alkaline extract of the reaction mixture for torasemide synthesis (1000 ml) prepared according to DE 25 16 025 was acidified with 10% aqueous acetic acid solution under the addition of 1.4 g of a crystal modification III of torasemide.
  • the suspension was stirred at room temperature for 90 minutes.
  • the crystals were sucked off, washed with 1 litre of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 125 g of a crystal modification III of torasemide, m.p. 162-165°C.
  • the X-ray powder pattern of the thus obtained sample corresponded to the new crystal modification III of torasemide.
  • the content of torasemide according to the HPLC method was >99%.
  • the crystal modification III of torasemide (1000 g) prepared according to the Example 1 was dissolved in a 10-fold amount of 5% aqueous potassium hydroxide solution and at the temperature of 20°C the obtained solution was acidified with 5% aqueous hydrochloric acid solution under the addition of 10 g of a crystal modification III of torasemide.
  • the suspension was stirred at 20°C for 120 minutes.
  • the crystals were sucked off, washed with 4 litres of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 961 g of a modification III of torasemide, m.p. 165°C.
  • the X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide.
  • the content of torasemide according to the HPLC method was >99.5%, i.e. it corresponded to chemically pure torasemide.
  • the crystal modification I of torasemide (1.00 g) prepared according to Ada Cryst. B34 (1978), 1304-1310 was dissolved in a 10-fold amount of 10% aqueous sodium carbonate solution and at the temperature of 15°C the obtained solution was acidified with 5% aqueous sulfuric acid solution under the addition of 0.10 g of the modification III of torasemide.
  • the suspension was stirred at 15°C for 120 minutes.
  • the crystals were sucked off, washed with 4 ml of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 0.95 g of a crystal modification III of torasemide, m.p. 165-166°C.
  • the X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide.
  • the content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide.
  • the crystal modification II of torasemide (1.00 g) prepared according to Ada Cryst. B34 (1978), 1304-1310 was dissolved in a 10-fold amount of 10% aqueous pottasium carbonate solution and then at the temperature of 15°C the obtained solution was acidified with 5% aqueous nitric acid solution under the addition of 0.10 g of a modification III of torasemide.
  • the suspension was stirred at 15°C for 120 minutes.
  • the crystals were sucked off, washed with 4 ml of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 0.96 g of a crystal modification III of torasemide, m.p. 164-166°C.
  • the X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide.
  • the content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide.
  • the X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide.
  • the content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide.
  • the X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide.
  • the content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide.
  • the X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide.
  • the content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide.
  • the X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide.
  • the content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide.
  • a crystal modification I of torasemide (1.00 g) prepared according to Acta Cryst. B34 (1978), 1304-1310 was dissolved in a 10-fold amount of 10% aqueous potassium carbonate solution and then at the temperature of 15°C the obtained solution was stepwise acidified with 10% aqueous acetic acid solution under the simultaneous stepwise lowering of the temperature of the mixture to 0°C. At this temperature the suspension was stirred for 25 hours. The crystals were sucked off, washed with 4 ml of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 0.94 g of a crystal modification III of torasemide, m.p. 164-166°C. The X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide.
  • the content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide.
  • Torasemide of the crystal modification III was mixed with lactose and corn starch in a common manner, granulated with water, dried and sieved (granulate 1). Colloidal silicon dioxide and magnesium stearate were mixed, sieved and admixed into granulate 1. This mixture was then tabletized in a common manner. For the production of 100 000 tablets the following is required:
  • lactose Lactose
  • Lactose Lactose
  • corn starch Starch®
  • colloidal silicon dioxide Alignil 200®
  • magnesium stearate 40.00 g redistilled water 1.20 kg
  • Torasemide of crystal modification III was mixed with lactose and com starch and a part of magnesium stearate in a common manner. The mixture was compressed and sieved to obtain the desired grain size and distribution of grain size (granulate 1). Colloidal silicon dioxide and magnesium stearate were mixed, sieved and admixed into granulate 1. This mixture was then tabletized in a common manner. For the production of 100 000 tablets the following is required:
  • lactose Lactose
  • Lactose Lactose Extra Fine Crystal HMS® 2.0 kg com starch (Starch®) 7.7 kg colloidal silicon dioxide (Aerosil 200®) 0.2 kg magnesium stearate 0.1 kg
  • microcrystallinic modifications I, II and III of torasemide prepared according to Acta Cryst. B34 (1978), 1304-1310 and Example 1 were subjected to dissolution testing in water and in artificial intestinal juice at 37 °C (USP 23) and the results are reported in Tables 3 and 4.
  • Table 3 Dissolution test of torasemide in water (USP 23) (37 °C, 50 rpm, 1000 ml)

Abstract

The present invention relates to the characterization of a new crystal modification III of torasemide, to a process for the preparation thereof by the use of controlled acidifying of alkaline solutions of torasemide with inorganic or organic acids with or without addition of a crystal seed, to its use as a raw material for the preparation of the crystal modification I of torasemide and of pharmaceutically acceptable salts of torasemide as well as to pharmaceutical forms containing this new crystal modification III of torasemide.

Description

NEW CRYSTAL MODIFICATION I I I OF TORASEMIDE
International Patent Classification: C 07 D 213/70; A 61 K 31/44
The present invention relates to a new crystal modification of N-(l-methylethyl aminocarbonyl)-4-(3-methyl-phenylamino)-3-pyridinesulfonamide (in the further text of the application designated by its generic name 'Torasemide"), particularly to a new crystal modification III of torasemide. to processes for its preparation, to its use as a raw material for the preparation of the crystal modification I of torasemide and of pharmaceutically acceptable salts of torasemide as well as to pharmaceutical forms containing the said new modification III of torasemide as the active ingredient.
Torasemide is a compound with interesting pharmacological properties, which is described in DE patent 25 16 025 (Example 71). As a diuretic of Henle's loop it is useful as an agent for preventing heart or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris. asthma, hypertension, nephroedema, pulmonary edema, primary and secondary aldosteronism, Bartter's syndrome, tumours, glaucoma, decreasing of intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by trauma, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens.
The ability of a substance to exist in more than one crystal form is defined as polymorphism and these different crystal forms are named "polymorph modifications"' or "polymorphs". In general, polymorphism is affected by the ability of a molecule of a substance to change its conformation or to form different intermolecular or intramolecular interactions, particularly hydrogen bonds, which is reflected in different atom arrangements in the crystal lattices of different polymorphs. Polymorphism is found in several organic compounds. Among medicaments polymorphism is found in about 70% of barbiturates, 60% of sulfonamides and 60% of steroids and about 50% of medicaments of the said classes are not present on the market in their most stable forms (T. Laird, Chemical Development and Scale-up in the Fine Chemical Industry, Principles and Practices, Course Manual, Scientific Update, Wyvern Cottage, 1996).
The different polymorphs of a substance possess different energies of the crystal lattice and, thus, in solid state they show different physical properties such as form, density, melting point, colour, stability, dissolution rate, milling facility, granulation, compacting etc., which in medicaments may affect the possibility of the preparation of pharmaceutical forms, their stability, dissolution and bioavailability and, consequently, their action.
Polymorphism of medicaments is the object of studies of interdisciplinar expert teams [J. Haleblian, W. McCrone, J. Pharm. Sci. 58 (1969) 911 ; L. Borka, Pharm. Ada Helv. 66 (1991) 16; M. Kuhnert-Brandstatter, Pharmazie 51 (1996) 443; H. G. Brittain, J Pharm. Sci. 86 (1997) 405; W. H. Streng, DDT 2 (1997) 415; K. Yoshii, Chem. Pharm. Bull. 45 (1997) 338, etc.] since a good knowledge of polymorphism represents a precondition for a critical observation of the whole process of medicament development. Thus, at deciding on the production of a pharmaceutical form in solid state and with regard to the dose size, stability, dissolution and anticipated action, it is necessary to determine the existence of all solid state forms (on the market some computer programmes can be found, e.g. »Polymorph« as a module of »Cerius2« programme, MSI Inc., USA) and to determine the stability, dissolution and thermodynamic properties of each of them. Only on the basis of these determinations the appropriate polymorph can be selected for the development of pharmaceutical formulations.
From the great number of such efforts only a few will be mentioned. Thus, Gordon et al. (US 4,476,248) protected a new crystal form of ibuprofen and a process for the preparation thereof; Bunnell et al. (EP 733 635) protected a new crystal form, a process for preparation thereof and a pharmaceutical formulation of the medicament olanzapine containing this new crystal form; R. B. Gandhi et al. (EP 749 969) protected a new process for the preparation of polymorph form I of stavudine from a mixture of one or more forms I, II and III; A. Caron et al. (EP 708 103) protected a new crystal form of irbesartane, a process for the preparation thereof and pharmaceutical formulations containing this crystal form.
It is known [Ada Cryst. B34 (1978), 2659-2662 and Ada Cryst. B34 (1978), 1304- 1310] that torasemide can exist in two crystal modifications differing with regard to the parameters of a single cell, which is confirmed by X-ray diffraction on their monocrystals. Both modifications are formed simultaneously by the slow evaporation of the solvent from a solution of torasemide in a mixture petroleum ether/ethanol. The modification I with melting point 169°C crystallizes monoclinically in the space group P 2[/c (prisms), while the modification II with melting point 162°C crystallizes monoclinically in the space group P 2/n (foils). Additionally, for the modification I the melting point 169.22°C is stated in Iyakuhin Kenkyu 25 (1994), 734-750.
According to Example 71 of DE 25 16 025 torasemide in a crystal form with melting point 163-164°C is obtained.
In US 4,743,693 and US reissue 34,580 or US 4,822,807 and US reissue 34,672 there is disclosed a process for the preparation of a stable modification I of torasemide from an unstable modification II of torasemide by adding a catalytic amount (1%) of a stable modification I of torasemide into a suspension of the unstable modification in water and stirring the mixture at a temperature from room temperature to 90°C within 3 hours to 14 days. In US 4,743,693 and US reissue 34,580 it is stated that the stable modification I of torasemide (monoclinic, space group P2t/c) has a melting point of 162°C and the unstable modification II of torasemide (monoclinic, space group P 2/n) has a melting point 169°C, which is contrary to the statements in A a Cryst. B34 (1978), 2659-2662, Ada Cryst. B34 (1978), 1304-1310 and Iyakuhin Kenkyu 25 (1994), 734-750. In the abstract of US 4,822,807 the authors ascribe the melting point 162°C to the stable polymorph I of torasemide and the melting point 169°C to the unstable polymorph II of torasemide, whereas in the claims of the said patent different melting points for either polymorph are stated, namely for polymorph I the melting point 169°C and for polymorph II the melting point 162°C.
In the abstract of US reissue 34,672 the authors ascribe the melting point 162°C to the pure modification I of torasemide and the melting point 169°C to the modification II of torasemide, whereas in the claims the melting point 159-161.5°C for the pure polymorph I and the melting point from about 157.5 to about 160°C for the unstable polymorph II are stated.
It has now been surprisingly found that by a controlled acidifying of alkaline solutions of torasemide with inorganic or organic acids with or without addition of a seed crystal at a temperature between 0 and 35°C within 15 minutes to 25 hours, a new crystal modification III of torasemide can be prepared.
By the alkaline solutions of torasemide according to the process of the present invention there are meant an alkaline extract of the original reaction mixture for the synthesis of torasemide, alkaline solutions of any crystal modification I, II or III of torasemide or alkaline solutions of any mutual mixtures of crystal modifications I, II or III of torasemide.
In the process of the present invention for the preparation of alkaline solutions of torasemide modifications, water solutions of lithium, sodium and potassium hydroxide as well as water solutions of sodium and potassium carbonate can be used.
The acidifying of the alkaline torasemide solutions according to the invention can be performed in inorganic acids such as hydrochloric, sulfuric, phosphoric and nitric acids and in organic acids such as formic, acetic, propionic, oxalic, tartaric, methanesulfonic and p-toluenesulfonic acids. As the seed crystal in the processes of the present invention crystal powder of one of the isostructure substances, particularly crystal powder of the crystal modification III of torasemide can be used.
It has additionally been found that by using the process of the present invention no decomposition of torasemide occurs and the impurities that may be present in the alkaline extract of the original reaction mixture for the synthesis of torasemide or in modifications I, II or III of torasemide pass, by the present process, into bases, i.e. a chemically pure crystal modification III of torasemide is obtained.
Moreover, it has been found that the new crystal modification III of torasemide is stable under normal storage conditions as well as at being subjected to increased humidity, which means that it is neither transformed into the unstable modification II of torasemide nor into the stable modification I of torasemide.
The new crystal modification III of torasemide has a characteristic X-ray powder pattern obtained by X-ray diffraction on a powder sample of the new crystal modification III of torasemide in the instrument PHILIPS PW3710 under Cu X-rays [- λ (CuKα = 1.54046 A and λ(CuKα2) = 1.54439 A]. Thus obtained characteristic spacings between lattice planes designated by »d« and expressed in Angstrom units and their corresponding characteristic relative intensities designated by »I/I0« and expressed in % are represented in Table 1.
Table 1
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
In addition, by recording the monocrystal of the new crystal modification III of torasemide in four circle PHILIPS PW HOO/Stoe&Cie diffractometer under Mo X- rays [λ (MoKα) = 0.71073 A] there were obtained the basic crystallographic data for a single cell, which show in comparison with the literature data for crystal modifications I and II of torasemide [Ada Cryst. B34 (1978), 2659-2662 and Ada Cryst. B34 (1978), 1304-1310] that this is an absolutely new crystal modification III of torasemide.
The basic crystallographic data (diffraction on monocrystal) for modifications I, II and the new crystal modification III of torasemide are represented in Table 2. Table 2
Figure imgf000011_0001
The new crystal modification III of torasemide prepared according to the process of the present invention can be transformed by the use of common processes to the crystal modification I of torasemide, i.e. it can be used as a starting material for the preparation of known crystal modification I of torasemide.
The new crystal modification III of torasemide prepared according to the invention can be transformed to pharmaceutically acceptable salts of torasemide by the use of common processes.
The dissolution profile (USP 23) of the new crystal modification III of toresamide in water and in artificial intestinal juice in comparison to dissolution profiles of known crystal modifications I and II of toresamide, in the same fluids, shows a significant difference.
IDR ( Intrinsic Dissolution Rate) of the new crystal modification III of torasemide in a model of artifical gastric juice exceeds 1 mg cm"2min"', which indicates a potential good bioavailability. The new crystal modification III of torasemide is prepared according to the process of the present invention in the form of a flowable crystal powder of a prismatic habitude, which exhibits flowability, i.e. it comes in a "free flow" form, wherein no static charge accumulation occurs.
The new crystal modification III of torasemide prepared according to the process of the present invention can be used as a suitable torasemide form as a diuretic as well as an agent for preventing heart or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris, asthma, hypertension, nephroedema, pulmonary edema, primary and secondary aldosteronism, Bartter's syndrome, tumours, glaucoma, for decreasing intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by trauma, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens.
The present invention also relates to pharmaceutical forms such as tablets containing the new crystal modification III of torasemide as the active ingredient combined with one or more pharmaceutically acceptable additives such as sugar, starch, starch derivatives, cellulose, cellulose derivatives, mould release agents, and antiadhesive agents and possibly agents for flowability regulation. When using the new crystal modification III of torasemide for the preparation of pharmaceutical forms, also process steps taking place in water, e.g. granulation, can be used.
The starting materials for the process of the present invention i.e. the alkaline extract of the original reaction mixture for torasemide synthesis can be prepared according to DE 25 16 025, whereas the modifications I and II of torasemide can be prepared according to Ada Cryst. B34 (1978), 1304-1310.
The present invention is illustrated but in no way limited by the following Examples. Example 1
Technically pure new crystal modification III of torasemide:
The original alkaline extract of the reaction mixture for torasemide synthesis (1000 ml) prepared according to DE 25 16 025 was acidified with 10% aqueous acetic acid solution under the addition of 1.4 g of a crystal modification III of torasemide. The suspension was stirred at room temperature for 90 minutes. The crystals were sucked off, washed with 1 litre of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 125 g of a crystal modification III of torasemide, m.p. 162-165°C.
The X-ray powder pattern of the thus obtained sample corresponded to the new crystal modification III of torasemide. The content of torasemide according to the HPLC method was >99%.
Example 2
The crystal modification III of torasemide (1000 g) prepared according to the Example 1 was dissolved in a 10-fold amount of 5% aqueous potassium hydroxide solution and at the temperature of 20°C the obtained solution was acidified with 5% aqueous hydrochloric acid solution under the addition of 10 g of a crystal modification III of torasemide. The suspension was stirred at 20°C for 120 minutes. The crystals were sucked off, washed with 4 litres of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 961 g of a modification III of torasemide, m.p. 165°C.
The X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide. The content of torasemide according to the HPLC method was >99.5%, i.e. it corresponded to chemically pure torasemide. Example 3
The crystal modification I of torasemide (1.00 g) prepared according to Ada Cryst. B34 (1978), 1304-1310 was dissolved in a 10-fold amount of 10% aqueous sodium carbonate solution and at the temperature of 15°C the obtained solution was acidified with 5% aqueous sulfuric acid solution under the addition of 0.10 g of the modification III of torasemide. The suspension was stirred at 15°C for 120 minutes. The crystals were sucked off, washed with 4 ml of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 0.95 g of a crystal modification III of torasemide, m.p. 165-166°C.
The X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide. The content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide.
Example 4
The crystal modification II of torasemide (1.00 g) prepared according to Ada Cryst. B34 (1978), 1304-1310 was dissolved in a 10-fold amount of 10% aqueous pottasium carbonate solution and then at the temperature of 15°C the obtained solution was acidified with 5% aqueous nitric acid solution under the addition of 0.10 g of a modification III of torasemide. The suspension was stirred at 15°C for 120 minutes. The crystals were sucked off, washed with 4 ml of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 0.96 g of a crystal modification III of torasemide, m.p. 164-166°C.
The X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide. The content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide. Example 5
A mixture of crystal modifications I and II of torasemide (1.00 g) prepared according to Ada Cryst. B34 (1978), 1304-1310 was dissolved in a 10-fold amount of 10% aqueous lithium hydroxide solution and then at room temperature the obtained solution was acidified with 5% aqueous phosphoric acid solution under the addition of 0.10 g of a modification III of torasemide. The suspension was stirred at 15°C for 240 minutes. The crystals were sucked off, washed with 4 ml of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 0.97 g of a crystal modification III of torasemide, m.p. 165-166°C.
The X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide. The content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide.
Example 6
A mixture of crystal modifications I and III of torasemide (1.00 g) prepared according to Ada Cryst. B34 (1978), 1304-1310 and Example 1 was dissolved in a 10-fold amount of 5% aqueous potassium hydroxide solution and then at the temperature of 30°C the obtained solution was acidified with 10 % aqueous tartaric acid solution under the addition of 0.10 g of a modification III of torasemide. The suspension was stirred at 30°C for 180 minutes. The crystals were sucked off, washed with 4 ml of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 0.93 g of a crystal modification III of torasemide, m.p. 164-166°C. The X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide. The content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide. Example 7
A mixture of crystal modifications II and III of torasemide (1.00 g) prepared according to Ada Cryst. B34 (1978), 1304-1310 and Example 1 was dissolved in a 10-fold amount of 5% aqueous sodium hydroxide solution and then at the temperature of 35°C the obtained solution was acidified with 5% aqueous propionic acid solution under the addition of 0.10 g of a modification III of torasemide. The suspension was stirred at 35°C for 90 minutes. The crystals were sucked off, washed with 4 ml of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 0.87 g of a crystal modification III of torasemide, m.p. 165°C.
The X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide. The content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide.
Example 8
A mixture of crystal modifications I, II and III of torasemide (1.00 g) prepared according to Ada Cryst. B34 (1978), 1304-1310 and Example 1 was dissolved in a 10- fold amount of 10% aqueous sodium carbonate solution and then at the temperature of 25°C the obtained solution was acidified with 5% aqueous p-toluenesulfonic acid solution under the addition of 0.10 g of a modification III of torasemide. The suspension was stirred at 25°C for 60 minutes. The crystals were sucked off, washed with 4 ml of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 0.93 g of a crystal modification III of torasemide, m.p. 164- 166°C.
The X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide. The content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide. Example 9
A crystal modification I of torasemide (1.00 g) prepared according to Acta Cryst. B34 (1978), 1304-1310 was dissolved in a 10-fold amount of 10% aqueous potassium carbonate solution and then at the temperature of 15°C the obtained solution was stepwise acidified with 10% aqueous acetic acid solution under the simultaneous stepwise lowering of the temperature of the mixture to 0°C. At this temperature the suspension was stirred for 25 hours. The crystals were sucked off, washed with 4 ml of demineralized water and dried in a vacuum dryer at 50°C for 3 hours. There were obtained 0.94 g of a crystal modification III of torasemide, m.p. 164-166°C. The X-ray powder pattern of the thus obtained sample corresponded to the crystal modification III of torasemide. The content of torasemide according to the HPLC method was >99,5%, i.e. it corresponded to chemically pure torasemide.
Example 10
Production of 2.5 mg tablets:
Torasemide of the crystal modification III was mixed with lactose and corn starch in a common manner, granulated with water, dried and sieved (granulate 1). Colloidal silicon dioxide and magnesium stearate were mixed, sieved and admixed into granulate 1. This mixture was then tabletized in a common manner. For the production of 100 000 tablets the following is required:
torasemide-crystal modification III 0.25 kg lactose (Lactose Extra Fine Crystal HMS®) 6.05 kg corn starch (Starch®) 1.60 kg colloidal silicon dioxide (Aerosil 200®) 60.00 g magnesium stearate 40.00 g redistilled water 1.20 kg
Example 11
Production of 100 mg tablets:
Torasemide of crystal modification III was mixed with lactose and com starch and a part of magnesium stearate in a common manner. The mixture was compressed and sieved to obtain the desired grain size and distribution of grain size (granulate 1). Colloidal silicon dioxide and magnesium stearate were mixed, sieved and admixed into granulate 1. This mixture was then tabletized in a common manner. For the production of 100 000 tablets the following is required:
torasemide-crystal modification III 10.0 kg lactose (Lactose Extra Fine Crystal HMS® 2.0 kg com starch (Starch®) 7.7 kg colloidal silicon dioxide (Aerosil 200®) 0.2 kg magnesium stearate 0.1 kg
Example 12
The microcrystallinic modifications I, II and III of torasemide prepared according to Acta Cryst. B34 (1978), 1304-1310 and Example 1 were subjected to dissolution testing in water and in artificial intestinal juice at 37 °C (USP 23) and the results are reported in Tables 3 and 4. Table 3: Dissolution test of torasemide in water (USP 23) (37 °C, 50 rpm, 1000 ml)
Figure imgf000019_0001
Table 4: Dissolution test of torasemide in artificial intestinal juice (USP 23) (37 °C, 50 rpm, pH 7.5, 1000 ml)
Figure imgf000019_0002
The results reported in Table 3 were plotted in Fig. 1. The results reported in Table 4 were plotted in Fig. 2.

Claims

Claims
1. New crystal modification III of torasemide, characterized in that the characteristic X-ray powder pattern of its sample is represented by the following spacings between lattice planes:
New crystal modification III of torasemide d(A)
15.3898
12.5973
11.4565
9.7973
9.5493
8.6802
8.2371
7.6351
7.3356
6.9759
6.5351
6.3240
6.1985
5.9521
5.6237
5.5623
5.4040
5.1119
4.8738 4.7865 4.6986 4.5985 4.4602 4.3405 4.2552 4.1829 4.0768 3.9377 3.8659 3.8429 3.7801 3.7248 3.6239 3.5556 3.4825 3.4130 3.3055 3.2298 3.1786 3.1278 3.0699 3.0078 2.9549 2.9056
2.8541
2.7686
2.6988
2.6610
2.6293
2.5549
2.5236
2.4485
2.4161
2.3671
2.3133
2.2788
2.2312
2.1852
2.1468
2.0957
2.0617
2.0273
1.9896
1.9688
1.9274
1.8853
1.7931
1.7449
1.7169
1.6512
1.6122
1.5601
1.5320
1.5057
Figure imgf000023_0001
2. New crystal modification III of torasemide according to claim 1, characterized in that in accordance with X-ray diffraction on its sample monocrystal it is represented by the following basis crystallographic data:
Figure imgf000023_0002
3. New crystal modification III of torasemide according to claims 1-2, characterized in that it is chemically pure.
4. New crystal modification III of torasemide according to claims 1-3, characterized in that it does not contain water.
5. New crystal modification III of torasemide according to claims 1-4, characterized in that it does not contain a solvent.
6. Process for the preparation of a new crystal modification III of torasemide according to claims 1-5, characterized in that an alkaline torasemide solution is subjected to controlled acidifying with inorganic or organic acids with or without addition of a seed crystal at a temperature between 0°C to 35°C within 15 minutes to 25 hours.
7. Process for the preparation of a new crystal modification III of torasemide according to claims 1-6, characterized in that as the alkaline torasemide solution an alkaline extract of the original reaction mixture for the synthesis of torasemide is used.
8. Process for the preparation of a new crystal modification III of torasemide according to claims 1-6, characterized in that as the alkaline torasemide solution an alkaline solution of any crystal modification I, II or III of torasemide or an alkaline solution of any mutual mixture of crystal modifications I, II or III of torasemide is used.
9. Process according to claims 1-8, characterized in that for the preparation of the alkaline torasemide solutions water solutions of lithium, sodium and potassium hydroxide and water solutions of sodium and potassium carbonate are used.
10. Process according to claims 1-9, characterized in that for acidifying inorganic acids such as hydrochloric, sulfuric, phosphoric or nitric acid or organic acids such as formic, acetic, propionic, oxalic, tartaric, methanesulfonic or p-toluensulfonic acid are used.
11. Process according to claims 1-10, characterized in that as the crystal seed crystal powder of one of the isocrystallinic substances is used, most preferably crystal powder of a crystal modification III of torasemide.
12. A new crystal modification III of torasemide according to claims 1-11, characterized in that it is used as a raw material for the preparation of crystal modification I of torasemide.
13. A new crystal modification III of torasemide according to claims 1-11, characterized in that it is used as a raw material for the preparation of pharmaceutically acceptable salts of torasemide.
14. A new crystal modification III of torasemide according to claims 1-11, characterized in that it is used as a form of torasemide as a diuretic, as an agent for preventing heart or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris, asthma, hypertension, nephroedema, pulmonary edema, primary and secondary aldosteronism, Bartter's syndrome, tumours, glaucoma, for decreasing intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by trauma, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens.
15. A pharmaceutical form, characterized in that it contains as the active ingredient the new crystal modification III of torasemide according to claims 1-11 combined for this purpose with pharmaceutically acceptable one or more carriers, additives or diluents.
16. A pharmaceutical form according to claim 15, characterized in that it is in tablet form.
PCT/HR1999/000023 1998-10-02 1999-10-01 New crystal modification iii of torasemide WO2000020395A1 (en)

Priority Applications (19)

Application Number Priority Date Filing Date Title
CA002345789A CA2345789A1 (en) 1998-10-02 1999-10-01 New crystal modification iii of torasemide
DE69922977T DE69922977C5 (en) 1998-10-02 1999-10-01 New crystal modification of Torasemid
EEP200100194A EE04341B1 (en) 1998-10-02 1999-10-01 Crystalline modification N of torasemide, process for its preparation, use and dosage form
JP2000574512A JP2002526532A (en) 1998-10-02 1999-10-01 A new crystalline N-form of torasemide
DK99949272T DK1117643T3 (en) 1998-10-02 1999-10-01 New crystal modification N of torasemide
UA2001031966A UA72895C2 (en) 1998-10-02 1999-10-01 A new crystal modification n of torasemide
AU62240/99A AU759291B2 (en) 1998-10-02 1999-10-01 New crystal modification N of torasemide
AT99949272T ATE286024T1 (en) 1998-10-02 1999-10-01 NEW CRYSTAL MODIFICATION OF TORASEMIDE
HU0104009A HUP0104009A3 (en) 1998-10-02 1999-10-01 New crystal modification of torasemide, process for its preparation, its use as a ran material and pharmaceutical compositions containing it
NZ510898A NZ510898A (en) 1998-10-02 1999-10-01 Crystal modification N of torasemide
IL14215099A IL142150A0 (en) 1998-10-02 1999-10-01 New crystal modification iii of torasemide
PL99346975A PL346975A1 (en) 1998-10-02 1999-10-01 New crystal modification iii of torasemide
SI9930744T SI1117643T1 (en) 1998-10-02 1999-10-01 New crystal modification n of torasemide
SK423-2001A SK4232001A3 (en) 1998-10-02 1999-10-01 New crystal modification iii of torasemide
EP99949272A EP1117643B1 (en) 1998-10-02 1999-10-01 New crystal modification n of torasemide
BR9915018-2A BR9915018A (en) 1998-10-02 1999-10-01 Crystal modification of torasemide
NO20011633A NO317107B1 (en) 1998-10-02 2001-03-30 New crystal modification of torasemide, process for its preparation, and pharmaceutical composition
BG105485A BG105485A (en) 1998-10-02 2001-05-02 New crystal modification n of torasemide
HK02102011.9A HK1040250B (en) 1998-10-02 2002-03-15 New crystal modification n of torasemide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HR980532A HRP980532B1 (en) 1998-10-02 1998-10-02 Novel crystalline torasemide modification
HRP980532A 1998-10-02

Publications (1)

Publication Number Publication Date
WO2000020395A1 true WO2000020395A1 (en) 2000-04-13

Family

ID=10946825

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HR1999/000023 WO2000020395A1 (en) 1998-10-02 1999-10-01 New crystal modification iii of torasemide

Country Status (32)

Country Link
US (5) US6399637B1 (en)
EP (1) EP1117643B1 (en)
JP (1) JP2002526532A (en)
KR (1) KR100437307B1 (en)
CN (1) CN1125049C (en)
AT (1) ATE286024T1 (en)
AU (1) AU759291B2 (en)
BG (1) BG105485A (en)
BR (1) BR9915018A (en)
CA (1) CA2345789A1 (en)
CZ (1) CZ20011031A3 (en)
DE (2) DE69922977C5 (en)
DK (1) DK1117643T3 (en)
EE (1) EE04341B1 (en)
ES (1) ES2237158T3 (en)
HK (1) HK1040250B (en)
HR (1) HRP980532B1 (en)
HU (1) HUP0104009A3 (en)
ID (1) ID29931A (en)
IL (1) IL142150A0 (en)
NO (1) NO317107B1 (en)
NZ (1) NZ510898A (en)
PL (1) PL346975A1 (en)
PT (1) PT1117643E (en)
RU (1) RU2210569C2 (en)
SI (1) SI1117643T1 (en)
SK (1) SK4232001A3 (en)
TR (1) TR200100909T2 (en)
UA (1) UA72895C2 (en)
WO (1) WO2000020395A1 (en)
YU (1) YU24001A (en)
ZA (1) ZA200102451B (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1117643A1 (en) 1998-10-02 2001-07-25 Pliva, Farmaceutska, Industrija, Dionicko Drustvo New crystal modification n of torasemide
WO2001070694A1 (en) * 2000-03-20 2001-09-27 Pliva D.D. Amorphous torasemide modification
WO2001087841A1 (en) * 2000-05-19 2001-11-22 Pliva, Farmaceutska Industrija, Dioničko Dručtvo Novel polymorph v of torasemide
EP1207880A1 (en) * 1999-08-11 2002-05-29 Teva Pharmaceutical Industries Ltd. Torsemide polymorphs
WO2004009554A1 (en) * 2002-07-19 2004-01-29 Pliva Hrvatska D.O.O. Process for the preparation of modification i of n-(1-methylethylaminocarbonyl)-4-(3-methylphenylamino)-3-pyridinesulfonamide
WO2004089904A2 (en) * 2003-04-07 2004-10-21 Torcan Chemical Ltd. Preparation of torasemide
US7002018B2 (en) 2001-08-03 2006-02-21 Ranbaxy Laboratories Limited Process for the preparation of amorphous form of torsemide
WO2008102240A1 (en) * 2007-02-20 2008-08-28 Toyota Jidosha Kabushiki Kaisha Stripping agent for secondary battery electrode material and method of treating secondary battery using the stripping agent
EP2705843A1 (en) * 2012-09-05 2014-03-12 Pharnext Therapeutic approaches for treating epilepsy and related disorders through reduction of epileptogenesis
CN104370805A (en) * 2013-08-13 2015-02-25 天津汉瑞药业有限公司 Torasemide compound

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6394707B1 (en) 1997-05-08 2002-05-28 Jack Kennedy Metal Products & Buildings, Inc. Yieldable mine roof support
DE10013289A1 (en) * 2000-03-17 2001-09-20 Knoll Ag Storage-stable formulations containing diuretic torasemide, are solids or semi-solids containing the active agent in non-crystalline form, e.g. as solid solution in vinyl pyrrolidone polymer matrix
US20050065183A1 (en) * 2003-07-31 2005-03-24 Indranil Nandi Fexofenadine composition and process for preparing
PL1750862T3 (en) 2004-06-04 2011-06-30 Teva Pharma Pharmaceutical composition containing irbesartan
CN106038500A (en) * 2016-05-26 2016-10-26 南京正科医药股份有限公司 Torasemide tablet
CN115417810B (en) * 2022-09-22 2023-10-10 南京正科医药股份有限公司 Refining method of torsemide crystal form I
CN117486789A (en) * 2023-12-29 2024-02-02 江西中医药大学 Torase Mi Gongjing salt and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0212537A1 (en) * 1985-08-17 1987-03-04 Roche Diagnostics GmbH Process for the preparation of a stable modification of torasemide, and medicaments containing torasemide
US5914336A (en) * 1998-06-02 1999-06-22 Boehringer Mannheim Gmbh Method of controlling the serum solubility of orally administered torasemide and composition relating thereto

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1477664A (en) * 1974-04-17 1977-06-22 Christiaens Sa A Pyridine derivatives
US4055650A (en) * 1974-04-17 1977-10-25 A. Christiaens Societe Anonyme Certain 4-phenoxy(or phenylthio)-3-n-acylated-sulfonamido-pyridines
US4473693A (en) 1978-08-04 1984-09-25 Stewart Walter W Aminonaphthalimide dyes for intracellular labelling
US6166041A (en) * 1995-10-11 2000-12-26 Euro-Celtique, S.A. 2-heteroaryl and 2-heterocyclic benzoxazoles as PDE IV inhibitors for the treatment of asthma
HRP980532B1 (en) 1998-10-02 2005-06-30 Pliva Novel crystalline torasemide modification
US6166045A (en) * 1998-06-02 2000-12-26 Roche Diagnostics Gmbh Torasemide of modification III

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0212537A1 (en) * 1985-08-17 1987-03-04 Roche Diagnostics GmbH Process for the preparation of a stable modification of torasemide, and medicaments containing torasemide
US5914336A (en) * 1998-06-02 1999-06-22 Boehringer Mannheim Gmbh Method of controlling the serum solubility of orally administered torasemide and composition relating thereto

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DUPONT L. ET AL.: "Structure cristalline et moléculaire d'un diurétique dérivé de l'alkyl-1[(phénylamino-4-pyridyl-3)sulfonyl]-3 urée: la torasémide (C15H20N4SO3)", ACTA CRYSTALLOGRAPHICA, SECTION B, vol. B34, no. 4, April 1978 (1978-04-01), pages 1304 - 1310, XP002128455 *
DUPONT L. ET AL.: "Structure d'une seconde variété de la torasémide", ACTA CRYSTALLOGRAPHICA, SECTION B, vol. B34, no. 8, August 1978 (1978-08-01), pages 2659 - 2662, XP002128456 *
KONDO N. ET AL.: "Chemical structure and physico-chemical properties of torasemide", IYAKUHIN KENKYU, vol. 25, no. 9, September 1994 (1994-09-01), pages 734 - 750, XP002128457 *
MASEREEL B. ET AL.: "Synthesis and pharmacology of pyrid-3-ylsulfonylcyanoguanidines as diuretics", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY.CHIMICA THERAPEUTICA,FR,EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, vol. 30, no. 4, April 1995 (1995-04-01), pages 343 - 351, XP004040154, ISSN: 0223-5234 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1117643A1 (en) 1998-10-02 2001-07-25 Pliva, Farmaceutska, Industrija, Dionicko Drustvo New crystal modification n of torasemide
EP1207880A1 (en) * 1999-08-11 2002-05-29 Teva Pharmaceutical Industries Ltd. Torsemide polymorphs
LT5004B (en) 1999-08-11 2003-03-25 Teva Pharmaceutical Industries Ltd. Torsemide polymorphs
EP1207880A4 (en) * 1999-08-11 2004-09-01 Teva Pharma Torsemide polymorphs
WO2001070694A1 (en) * 2000-03-20 2001-09-27 Pliva D.D. Amorphous torasemide modification
US6767917B1 (en) 2000-03-20 2004-07-27 Pliva D.D. Amorphous torasemide modification
WO2001087841A1 (en) * 2000-05-19 2001-11-22 Pliva, Farmaceutska Industrija, Dioničko Dručtvo Novel polymorph v of torasemide
US7241782B1 (en) 2000-05-19 2007-07-10 Pliva, Farmaceutska Industrija, Dionicko Drustvo Polymorph V of torasemide
US7002018B2 (en) 2001-08-03 2006-02-21 Ranbaxy Laboratories Limited Process for the preparation of amorphous form of torsemide
WO2004009554A1 (en) * 2002-07-19 2004-01-29 Pliva Hrvatska D.O.O. Process for the preparation of modification i of n-(1-methylethylaminocarbonyl)-4-(3-methylphenylamino)-3-pyridinesulfonamide
WO2004089904A2 (en) * 2003-04-07 2004-10-21 Torcan Chemical Ltd. Preparation of torasemide
WO2004089904A3 (en) * 2003-04-07 2004-12-23 Torcan Chemical Ltd Preparation of torasemide
WO2008102240A1 (en) * 2007-02-20 2008-08-28 Toyota Jidosha Kabushiki Kaisha Stripping agent for secondary battery electrode material and method of treating secondary battery using the stripping agent
KR101097555B1 (en) 2007-02-20 2011-12-22 도요타지도샤가부시키가이샤 Stripping agent for secondary battery electrode material and method of treating secondary battery using the stripping agent
US8404138B2 (en) 2007-02-20 2013-03-26 Toyota Jidosha Kabushiki Kaisha Stripping agent for secondary battery electrode material and method of treating secondary battery using the stripping agent
EP2705843A1 (en) * 2012-09-05 2014-03-12 Pharnext Therapeutic approaches for treating epilepsy and related disorders through reduction of epileptogenesis
WO2014037417A1 (en) * 2012-09-05 2014-03-13 Pharnext Therapeutic approaches for treating epilepsy and related disorders through reduction of epileptogenesis
CN104370805A (en) * 2013-08-13 2015-02-25 天津汉瑞药业有限公司 Torasemide compound

Also Published As

Publication number Publication date
HUP0104009A3 (en) 2002-04-29
ES2237158T3 (en) 2005-07-16
KR20010079962A (en) 2001-08-22
YU24001A (en) 2003-02-28
PL346975A1 (en) 2002-03-11
DK1117643T3 (en) 2005-03-29
PT1117643E (en) 2005-05-31
US6399637B1 (en) 2002-06-04
DE69922977C5 (en) 2008-12-24
DE69922977T2 (en) 2005-12-08
AU6224099A (en) 2000-04-26
CN1125049C (en) 2003-10-22
RU2210569C2 (en) 2003-08-20
US20040229919A1 (en) 2004-11-18
TR200100909T2 (en) 2001-07-23
EP1117643B1 (en) 2004-12-29
US20020147346A1 (en) 2002-10-10
CZ20011031A3 (en) 2001-08-15
AU759291B2 (en) 2003-04-10
ATE286024T1 (en) 2005-01-15
NO20011633L (en) 2001-03-30
HUP0104009A2 (en) 2002-02-28
EP1117643A1 (en) 2001-07-25
JP2002526532A (en) 2002-08-20
DE29924789U1 (en) 2005-08-25
ID29931A (en) 2001-10-25
NO20011633D0 (en) 2001-03-30
SK4232001A3 (en) 2001-10-08
HK1040250B (en) 2004-03-05
BR9915018A (en) 2001-08-14
CA2345789A1 (en) 2000-04-13
DE69922977D1 (en) 2005-02-03
EE200100194A (en) 2002-06-17
EE04341B1 (en) 2004-08-16
ZA200102451B (en) 2001-09-28
US20060205951A1 (en) 2006-09-14
UA72895C2 (en) 2005-05-16
CN1321149A (en) 2001-11-07
IL142150A0 (en) 2002-03-10
SI1117643T1 (en) 2005-06-30
NO317107B1 (en) 2004-08-09
US20070276015A1 (en) 2007-11-29
NZ510898A (en) 2002-10-25
BG105485A (en) 2002-01-31
HK1040250A1 (en) 2002-05-31
US20030055258A2 (en) 2003-03-20
KR100437307B1 (en) 2004-06-25
HRP980532A2 (en) 2000-12-31
US6833379B2 (en) 2004-12-21
HRP980532B1 (en) 2005-06-30

Similar Documents

Publication Publication Date Title
US20060205951A1 (en) New crystal modification of torasemide
US20070238759A1 (en) Novel Polymorph V of Torasemide
JPH0415205B2 (en)
EP1272470B1 (en) Amorphous torasemide modification
MXPA01003325A (en) New crystal modification iii of torasemide
EP1334726A1 (en) Erythromycin derivative having novel crystal structures and processes for their production

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: P-240/01

Country of ref document: YU

Ref document number: 99811710.2

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 142150

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: PV2001-1031

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: 4232001

Country of ref document: SK

WWE Wipo information: entry into national phase

Ref document number: 2001/02451

Country of ref document: ZA

Ref document number: 200102451

Country of ref document: ZA

ENP Entry into the national phase

Ref document number: 2345789

Country of ref document: CA

Ref document number: 2345789

Country of ref document: CA

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2000 574512

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/2001/003325

Country of ref document: MX

Ref document number: 1020017004079

Country of ref document: KR

Ref document number: 2001/00909

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 510898

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 1999949272

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 62240/99

Country of ref document: AU

Ref document number: IN/PCT/2001/583/CHE

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 20010352

Country of ref document: UZ

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 1999 105485

Country of ref document: BG

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 1999949272

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV2001-1031

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1020017004079

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 62240/99

Country of ref document: AU

WWG Wipo information: grant in national office

Ref document number: 1020017004079

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 1999949272

Country of ref document: EP